Since its discovery in 1971, paclitaxel (sold under the trade name Taxol®) (Formula 1) has become a powerful and widely used anticancer agent. Its unique
bioactivity promotes the assembly and stabilization of intracellular structures called microtubules. Microtubules are dynamic structures that are constantly being broken down and reformed within living cells. A notable structure involving microtubules is the mitotic spindle used by eukaryotic cells to segregate their chromosomes during cell division. The formation and subsequent degradation of the mitotic spindle is critical to the normal progression of mitosis. In the presence of paclitaxel, however, the stabilized microtubules cannot retract after chromosomal separation and cellular mitosis is terminated.
Paclitaxel successfully treats a number of cancers, including breast, ovarian and lung carcinomas. Additionally, paclitaxel has demonstrated efficacy in treating cancers resistant to other therapies, has been used to inhibit smooth muscle cell proliferation and migration for treatment of restinosis, and further applications of paclitaxel are presently under investigation. Enormous clinical success has made paclitaxel the focus of many studies.
Paclitaxel is known to occur in at least two crystalline forms: an anhydrate and a trihydrate. The occurrence of different crystalline forms (i.e., polymorphism) is a property of some molecules and molecular complexes. A single molecule, or a salt complex, may give rise to a variety of solids having distinct physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint and various NMR spectra. The differences in the physical properties of different crystalline forms result from the orientation and intermolecular interactions of adjacent molecules (complexes) in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous and/or disadvantageous physical properties compared to other forms in the polymorph family. These properties can be influenced by controlling the conditions under which the solid form of a material is obtained.
Purified, anhydrous paclitaxel has been found to undergo degradation, even under controlled storage conditions. However, it has been found that paclitaxel trihydrate is considerably more stable than the anhydrate, which allows the trihydrate to retain its anti-cancer properties for longer compared to the anhydrate. Likewise, paclitaxel trihydrate may be more soluble than the anhydrate, which may lead to better drug delivery.
U.S. Pat. No. 6,002,022 to Authelin et al. describes a method for making the only known paclitaxel trihydrate form. The trihydrate described in the Authelin patent has a stability that is markedly superior to that of the anhydrous product. According to Authelin et al., paclitaxel trihydrate is obtained by recrystallization of paclitaxel from a mixture of water and an aliphatic alcohol containing up to three carbon atoms, specifically methanol. The water/alcohol weight ratio used in this process is between 3/1 to 1/3. The crystals, thus obtained, are dried at about 40° C. under reduced pressure. A nuclear magnetic resonance (“NMR”) spectrum of the paclitaxel trihydrate crystalline polymorph described in Authelin et al. is illustrated herein in FIG. 1 as Taxol trihydrate I. Peak assignments associated with Taxol trihydrate I are listed in Table 5 in the column labeled Phase I δ13C.
The discovery of new forms of a pharmaceutically useful compound provides an opportunity, to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. Additional polymorphic forms may further help in determination of polymorphic content of a batch of an active pharmaceutical ingredient, for example, by providing a useful reference standard for XRD instruments.